title: Metabolism of a dopamine receptor partial agonist in rats, including an unusual N-dearylation reaction.
abstract: The metabolism of 3,4-dihydro-7-[4-(1-naphthalenyl)-1-piperazinyl]butoxy]-1,8-naphthyridin-2(1H)-one (NPBN) was investigated in rats. Animals were administered 30 mg/kg NPBN that was labeled with both tritium and carbon-14. The mass recovery of drug-related material was 96-98%, with almost all material excreted in feces. Metabolism occurred by oxidation reactions followed by conjugation. The main route of metabolism of NPBN occurred via oxidation of the naphthylene ring, which led to naphthol and dihydrodiol metabolites as well as a relatively novel N-dearylated metabolite in which the naphthylene ring was removed. In vitro investigation in rat liver microsomes also showed a glutathione adduct on the naphthalene and a glutathione adduct of naphthoquinone, which, along with the dihydrodiol metabolite, is consistent with the initial generation of an epoxide. A mechanism is proposed whereby the N-dearylation arises via epoxidation, followed by formation of an exocyclic iminium ion intermediate that is hydrolyzed to yield the N-dearylated metabolite. An additional mechanism involves oxidation of the naphthol metabolite via a radical mechanism, since this metabolite was also shown to undergo N-dearylation.
authors.affiliation: Pfizer Inc., Groton, U.S.
authors.forename: Sabrina X
authors.initials: SX
authors.lastname: Zhao
authors.forename: Wendy Weiwei
authors.initials: WW
authors.lastname: Wang
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Walker
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
authors.forename: R Scott
authors.initials: RS
authors.lastname: Obach
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D003640:Dealkylation; D018492:Dopamine Antagonists / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D065127:Dopamine D2 Receptor Antagonists; D054333:Drug Partial Agonism; D004852:Epoxy Compounds / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D005260:Female; D020719:Glucuronides / Q000097:blood / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D006900:Hydroxylation; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D009287:Naphthyridines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D010084:Oxidation-Reduction; D010879:Piperazines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D013463:Sulfuric Acid Esters / Q000378:metabolism; D014556:Urine / Q000737:chemistry
chemical_list: D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D004852:Epoxy Compounds; D020719:Glucuronides; D009287:Naphthyridines; C560205:PF 00217830; D010879:Piperazines; D013463:Sulfuric Acid Esters; D005978:Glutathione